ABSTRACT Glioblastoma (GBM) is the most common primary brain tumor and one of the most lethal of all cancers. The main challenge in treating GBM is the quickly developing resistance to all kinds of treatments by tumor cells. Whereas our partial understanding of GBM biology is a major roadblock to elucidate the underlying resistance mechanisms. Our laboratory recently uncovered that GBM greatly alters lipid metabolism to gain sufficient lipids for its rapid growth. We identified that sterol regulatory element-binding protein-1 (SREBP-1), a master transcription factor that controls fatty acid synthesis, is highly expressed in GBM and is essential for tumor growth. Our findings were recently validated by multiple groups showing that SREBP-1 is also elevated in various other cancers. However, whether the dramatically altered lipid metabolism facilitates tumor resistance is completely unknown. Moreover, the mechanism that upregulates SREBP-1 expression in cancer cells remains elusive. Interestingly, we recently found that all-trans retinoic acid (ATRA) and 13-cis-RA could significantly reduce the expression of SREBP-1 and lipogenic enzymes in a dose-dependent manner in GBM cells. These retinoic acids are effective drugs in treating acute promyelocytic leukemia and have also been used to treat GBM and other solid tumors, but tumor resistance has been very challenging. To date, both their antitumor and resistance mechanisms remain poorly understood. We examined the expression of their binding partner, retinoic acid nuclear receptor ? (RAR?) in GBM patient tissues and found it to be highly expressed in tumor tissues and positively correlated with SREBP-1 expression, while inversely associated with poor patient survival. Interestingly, our data further show that 13-cis-RA and ATRA treatment significantly increased the expression of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme shuttling fatty acids into mitochondria for ?-oxidation and energy production. Pharmacological inhibition of CPT1A combined with retinoic acid treatment resulted in marked GBM cell death. Together, these novel preliminary data strongly support the hypothesis that 13-cis-RA or ATRA can significantly alter lipid metabolism in GBM and promote fatty acid oxidation to support tumor cell survival and resistance. We further hypothesize that retinoic acid treatment in combination with suppression of SREBP-1 activation or fatty acid oxidation will effectively inhibit GBM growth and overcome tumor resistance. The goal of this study is to identify the previously unreported roles and mechanisms of retinoic acids and RAR? in lipid metabolism regulation and GBM growth (Aim 1), and to develop effective combination approaches to target GBM (Aim 2). Completion of this study will uncover the underlying mechanism upregulating SREBP-1 expression and lipogenesis in GBM, provide great insights into understanding the antitumor and resistance mechanisms of retinoic acids, and identify novel strategies to target GBM and overcome retinoic acid resistance.